Magnesium hydroxide temporarily enhancing osteoblast activity and decreasing the osteoclast number in peri-implant bone remodelling

Repeated observations of enhanced bone growth around various degradable magnesium alloys in vivo raise the question: what is the major mutual origin of this biological stimulus? Several possible origins, e.g. the metal surface properties, electrochemical interactions and biological effects of alloying elements, can be excluded by investigating the sole bone response to the purified major corrosion product of all magnesium alloys, magnesium hydroxide (Mg(OH)₂). Isostatically compressed cylinders of pure Mg(OH)₂ were implanted into rabbit femur condyles for 2–6 weeks. We observed a temporarily increased bone volume (BV/TV) in the vicinity of Mg(OH)₂ at 4 weeks that returned to a level that was equal to the control at 6 weeks. The osteoclast surface (OcS/BS) was significantly reduced during the first four weeks around the Mg(OH)₂ cylinder, while an increase in osteoid surface (OS/BS) was observed at the same time. At 6 weeks, the OcS/BS adjacent to the Mg(OH)₂ cylinder was back within the same range of the control. The mineral apposition rate (MAR) was extensively enhanced until 4 weeks in the Mg(OH)₂ group before matching the control. Thus, the enhanced bone formation and temporarily decreased bone resorption resulted in a higher bone mass around the slowly dissolving Mg(OH)₂ cylinder. These data support the hypothesis that the major corrosion product Mg(OH)₂ from any magnesium alloy is the major origin of the observed enhanced bone growth in vivo. Further studies have to evaluate if the enhanced bone growth is mainly due to the local magnesium ion concentration or the local alkalosis accompanying the Mg(OH)₂ dissolution.     

细菌性脑膜炎病原菌分布及抗生素应用与耐药的关系

目的了解细菌性脑膜炎病原菌的分布特点以及抗生素应用与耐药性的关系,为临床合理选用抗生素治疗提供依据。方法对某医院新生儿科2000年1月-2005年12月临床诊断为细菌性脑膜炎患儿的脑脊液进行普通培养和高渗培养,用法国生物梅里埃系统鉴定细菌,以K-B法进行药敏分析。结果有156份脑脊液培养出了病原菌,主要为表皮葡萄球菌、大肠埃希菌、溶血葡萄球菌。早期新生儿组革兰阴性杆菌检出率比晚期新生儿组高,晚期新生儿组革兰阳性球菌检出率比早期新生儿组高。革兰阴性杆菌对亚胺培南、头孢曲松、头孢哌酮等较敏感,革兰阳性球菌对头孢噻肟、头孢哌酮、头孢曲松等较敏感;使用过抗生素患儿检出产耐药酶菌的比率明显高于未使用过抗生素患儿(χ2=7.68,P<0.05),尤其使用过第三代头孢菌素的患儿检出产耐药酶菌的比率显著高于后者(χ2=10.04,P<0.005)。结论新生儿细菌性脑膜炎病原菌以革兰阳性球菌为主,其分布与新生儿肺炎病原菌有相关性。合理应用抗生素尤其第三代头孢菌素,减少耐药菌株的产生。     

Systemic treatment of patients with gastrointestinal stromal tumor: Current status and future opportunities

Imatinib mesylate is considered the standard first-line systemic treatment for patients with advanced gastrointestinal stromal tumor (GIST). Results from recent research have expanded the knowledge of tyrosine kinase inhibitors in management of GIST. In the setting of unresectable and metastatic GIST, long-term follow-up of the B2222 study showed that imatinib 400 and 600 mg/d produced objective responses in 68% of patients and clinical benefit in 84%; it also extended median survival from 19 months in historical controls to 57 months. The MetaGIST analysis in two large phase 3 trials consisting of more than 1600 patients with metastatic and/or unresectable GIST showed that imatinib 800 mg/d compared with the standard 400-mg/d dose conferred a progression-free survival advantage in patients with KIT exon 9 mutations but not in other subpopulations. The higher starting dose does not significantly improve overall survival. The BFR14 trial demonstrated that interrupting imatinib is associated with a high risk of rapid disease progression. For patients with imatinib-intolerant or imatinib-resistant GIST, sunitinib or a variety of investigational agents, including the next-generation kinase inhibitor nilotinib, may be viable options for achieving disease control. In the setting of primary localized GIST, function- sparing surgical resection is the standard treatment approach, but some patients may be at substantial risk of disease recurrence and metastasis depending on tumor size, mitotic count, and possibly other factors. Initial results from ACOSOG Z9001 indicate that adjuvant imatinib for 1 year prolongs recurrence-free survival following surgical resection of larger (at least 3 cm) KIT-expressing GIST. Other ongoing studies are further exploring the role of imatinib in both adjuvant and neoadjuvant therapy. Recent updates to clinical practice guidelines and recommendations now incorporate some of these new findings.     

First case of Tropicoporus tropicalis keratitis in an immunocompetent host from India and review of the literature

Tropicoporus tropicalis is an environmental basidiomycete that has been implicated in nine cases of cutaneous (n = 7) and pulmonary (n = 2) human infections predominantly in chronic granulomatous disease patients. We report here the first case of keratitis caused by Tropicoporus tropicalis in a 40-year-old immunocompetent patient, who presented with sudden diminution of vision in right eye. Corneal scrapings revealed hyaline, septate hyphae in microscopy and culture showed growth of white non-sporulating mycelial growth which was confirmed as Tropicoporus tropicalis by sequencing of ITS region of 28S rDNA. The patient was initiated on topical voriconazole along with natamycin, gatifloxacin and atropine drops. However, despite treatment, corneal ulcer perforated, for which penetrating keratoplasty was performed. Thereafter, he was prescribed amphotericin B (AMB) drops sixteen times a day and ketoconazole 200 mg twice a day with no recurrence reported over one year of follow up. The case represents the first case of infection by this fungus from India and also is the first case to be reported in an immunocompetent host.     

Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest

PurposeThe genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test.MethodsThrough comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes.ResultsA total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T [p.Arg1381], c.282C>A [p.Cys941]; c.257dup [p.Tyr861]; and c.180del, [p.Ser61Profs130]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes.ConclusionBy combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest.     

Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome

PurposeRABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1.MethodsThrough GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing. We established lymphoblastoid cells lines derived from an affected individual and her parents and performed RNA sequencing and functional studies. Rabgap1 knockout mice were generated and phenotyped.ResultsWe report 5 patients presenting with a common constellation of features, including global developmental delay/intellectual disability, microcephaly, bilateral sensorineural hearing loss, and seizures, as well as overlapping dysmorphic features. Neuroimaging revealed common features, including delayed myelination, white matter volume loss, ventriculomegaly, and thinning of the corpus callosum. Functional analysis of patient cells revealed downregulated mTOR signaling and abnormal localization of early endosomes and lysosomes. Rabgap1 knockout mice exhibited several features in common with the patient cohort, including microcephaly, thinning of the corpus callosum, and ventriculomegaly.ConclusionCollectively, our results provide evidence of a novel neurodevelopmental syndrome caused by biallelic loss-of-function variants in RABGAP1.